The Pima Indians of Arizona have the highest reported prevalence and incidence of non-insulin dependent diabetes mellitus (NIDDM) of any population in the world. Beginning in 1982, our section has studied a subset of this population to determine the etiologic factors that predispose non-diabetic individuals to develop the disease. Subjects are admitted yearly to the clinical research ward to undergo body composition analysis, an oral glucose tolerance test, an intravenous glucose tolerance test, a standard mixed meal test, and a two-step hyperinsulinemic, euglycemic clamp to measure insulin action in vivo. Over 600 individuals have entered into the study and approximately 50 subjects have developed NIDDM. Obesity, central obesity, fasting hyperinsulinemia, and insulin resistance are each major risk factors for the developement of NIDDM. The acute insulin response to a intravenous glucose bolus is an additional, but weaker predictor. Since each of these factors are familial and predictive of diabetes, it is likely that the genetic determinants of these phenotypes contribute to the pathogenesis of NIDDM, which is known to be largely genetically determined. Thus, current effort on this project is directed to recruiting and studying the siblings of individuals who have previously participated in these studies. The phenotypic information generated from these studies will be used in conjunction with DNA markers in sib-pair linkage analyses to identify loci linked to insulin resistance, decreased insulin secretory function and obesity.